5-135028801-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002653.5(PITX1):c.923A>G(p.Asn308Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,607,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PITX1
NM_002653.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.40

Publications

0 publications found

Variant links:

Genes affected

PITX1 (HGNC:9004): (paired like homeodomain 1) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. [provided by RefSeq, Jul 2008]

PITX1 Gene-Disease associations (from GenCC):

clubfoot
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
brachydactyly-elbow wrist dysplasia syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

PITX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25126463).

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX1	NM_002653.5 link	c.923A>G	p.Asn308Ser	missense_variant	Exon 3 of 3	ENST00000265340.12	NP_002644.4	P78337X5D9A5
PITX1	XM_047417318.1 link	c.1025A>G	p.Asn342Ser	missense_variant	Exon 4 of 4		XP_047273274.1
PITX1	XM_047417319.1 link	c.578A>G	p.Asn193Ser	missense_variant	Exon 3 of 3		XP_047273275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX1	ENST00000265340.12 link	c.923A>G	p.Asn308Ser	missense_variant	Exon 3 of 3	1	NM_002653.5	ENSP00000265340.6		P78337
PITX1	ENST00000506438.5 link	c.923A>G	p.Asn308Ser	missense_variant	Exon 4 of 4	1		ENSP00000427542.1		P78337

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00000843

AC:

AN:

237250

AF XY:

0.00000769

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1455722

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724072

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5110

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1110330

Other (OTH)

AF:

0.00

AC:

AN:

60052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67860

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 26, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

0.079

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.17

N;N

PhyloP100

7.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

1.2

N;N

REVEL

Uncertain

0.44

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.96

P;P

Vest4

0.21

MutPred

0.24

Gain of phosphorylation at Y312 (P = 0.107);Gain of phosphorylation at Y312 (P = 0.107);

MVP

0.81

MPC

0.84

ClinPred

0.25

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.30

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-135028801-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over